The Potential Roles of Osmotic and Nonosmotic Sodium Handling in Mediating the Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Heart Failure

Figures

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  Fig. 1.. Summary of hospitalization for heart failure results from recent cardiovascular safety trials of sodium-glucose cotransporter 2 (SGLT2) inhibitors. Values in brackets are 95% confidence intervals. Values were derived from the trials’ publications; slightly different terminology was used in the trials to describe heart failure hospitalization: EMPA-REG and DECLARE used “rate per 1000 pt-yrs,” CANVAS used “number of participants per 1000 pt-yrs,” and CREDENCE and DAPA-HF used “events per 1000 [or 100 for DAPA-HF] pt-yrs.” CANVAS, CANagliflozin cardioVascular Assessment Study; CREDENCE, Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DECLARE, Dapagliflozin Effect on Cardiovascular Events—Thrombolysis in Myocardial Infarction 58; EMPA-REG, EMPAgliflozin cardiovascular outcome event trial in type 2 diabetes mellitus patients—Removing Excess Glucose; HR, hazard ratio.

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  Fig. 2.. Schematic of a nephron and sodium-glucose cotransporter (SGLT) inhibitors. NHE3, Na+/H+ exchanger isoform 3; SGLT2, sodium-glucose cotransporter 2.

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  Fig. 3.. Plasma renin activity with sodium-glucose cotransporter 2 (SGLT2) inhibition. (A) Increase in plasma renin activity by 117% after 1 week of bumetanide treatment in healthy volunteers (adapted from Wilcox et al. 201841; see Supplementary Fig. S6; available at: https://www.ahajournals.org/doi/10.1161/JAHA.117.007046; used under CC BY-NC 4.0; text slightly updated, parts of panels A and B combined, layout altered, and color added). (B) Week 12 change from baseline in plasma renin activity in patients with type 2 diabetes (T2D) treated with dapagliflozin (DAPA) or hydrochlorothiazide (HCTZ) (based on data from: Heerspink et al. 201343, Table 2). (C) Changes in plasma volume markers during DAPA treatment vs placebo treatment in patients with T2D (P < .01) (adapted from: Eickhoff et al 2019,50 Fig. 2, fourth panel from the left; available at: https://www.mdpi.com/2077-0383/8/6/779; used under CC BY 4.0; text slightly updated, layout altered, and color added).

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  Fig. 4.. Putative sodium-centric mechanisms of benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors in people with type 2 diabetes (T2D) and cardiorenal disease. BP, blood pressure.